1. Field of the Invention
The present invention concerns phosphorylated derivatives of L-dopa and compositions containing the same and methods using such compositions for increasing the melanin content in mammalian skin and hair.
2. Background Information
U.S. Pat. No. 4,508,706 describes the preparation and use of phosphorylated derivatives of L-3,4-dihydroxyphenylalanine ("L-dopa" or "L-DOPA") wherein the phosphoryl groups are esterified via an oxygen linkage to either the 3' or 4' positions of the phenylalanine ring. These isomers are collectively referred to as "dopa phosphates" or "P-DOPA" or "p-dopa".
Using mouse melanoma cells in culture as a model it was found that at relatively high concentrations (10.sup.-4 -10.sup.-3 M) phosphates increase melanin formation and promote cytotoxicity (Pawelek J. and Murray M., Cancer Research, 46, 493-497, (1986)). It was shown that these effects were primarily due to the enzymatic removal of the phosphoryl groups and resultant production of L-dopa. It was well-established in many previous studies that L-dopa at high concentrations is cytotoxic to pigment-producing cells and also can be enzymatically converted into melanin by such cells (e.g., Pawelek J., J. Investigative Dermatology, 66, 201-209, (1976)).
Also using mouse melanoma cells in culture it was found that low concentrations of dopa phosphates (10.sup.-5 - 10.sup.-6 M) were not cytotoxic and by themselves had no noticeable affect on pigment production by the cells. However, at these low concentrations dopa phosphates stimulated a hormone binding system in the cells and increased the cellular responsiveness to the hormone "melanotropin" (also referred to as "melanocyte stimulating hormone" or "MSH") (McLane, J., Osber, M. and Pawelek, J., Biochem. Biophys. Research Communications, 145, 719-725, (1987)). An important finding to emerge from the studies on low concentrations of dopa phosphates was that L-dopa itself at such concentrations did not appear to stimulate the MSH binding system in the cells. These observations raised the possibility that the phosphoryl groups must remain esterified to L-dopa in order for there to be a stimulation of the MSH binding system.
Using hairless, pigmented mice and pigmented guinea pigs, it was found that dopa phosphates, but not L-dopa, increased pigmentation in the skin. This effect was best observed when the dopa phosphates were applied in conjunction with low levels of ultraviolet light (Pawelek J., et al, "Advances in Pigment Cell Research" in Progress in Clinical and Biological Research, Volume 256, J. E. Bagnara, ed., Alan R. Liss, Inc., N.Y., pp. 143-154, (1988); Agin P. P., Sayre R. M. and Pawelek J., Pigment Cell Research, 1, 137-142), (1987)).
Using melanoma cells in culture, mice, and guinea pigs, it was found that ultraviolet light appears to increase melanin content in mammalian skin by stimulating the MSH binding system, much the same as dopa phosphates (Bolognia, J., Murray M. and Pawelek J., J. Invest. Dermatology, in pres, (1989)).
EP 238,826 describes a skin-tanning composition containing an indole derivative.